Sfrp5 and Wnt5a: novel regulators of cytokine release and insulin action through the non-canonical Wnt-signalling pathway in primary human adipocytes and hepatocytes?
Final Report Abstract
This project revealed that serum levels of Sfrp5 and Wnt5a were not regulated by weight loss. Associations with inflammatory and metabolic parameters were not independent of other risk factors. Only the association between Sfrp5 and Wnt5a remained stable after adjustment for confounders which supported their strong interaction with each other. In addition, we found that Wnt5a might have an antiinflammatory phenotype in subcutaneous and visceral adipocytes as well as HepaRG cells. This was shown by Wnt5a-induced downregulation of pro-inflammatory proteins. In human HepaRG cells, the anti-inflammatory phenotype of Wnt5a might also be mediated by partial inactivation of NFκB. Interestingly, Sfrp5 reversed most of the Wnt5a-induced downregulations of pro-inflammatory proteins. In primary human adipocytes isolated from both subcutaneous and visceral adipose tissue, Sfrp5 and Wnt5a did not affect insulin signalling. In HepaRG cells, Wnt5a decreased insulin sensitivity whereas Sfrp5 had no impact on this process. In addition, Wnt5a increased the expression of gluconeogenic enzymes which might elevate the rate of gluconeogenesis and thereby contribute to reduced insulin sensitivity. Its antagonist Sfrp5 in turn counterregulated the elevation of these gluconeogenic enzymes and might thereby reverse insulin resistance. This is in line with the results from the population-based KORA study. High Sfrp5 levels were associated with lower odds of prediabetes/type 2 diabetes which was independent of confounders. Therefore, Sfrp5 might be protective in the development of prediabetes/type 2 diabetes by antagonising Wnt5a.
Publications
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Inverse associations between serum levels of secreted frizzled-related protein-5 (SFRP5) and multiple cardiometabolic risk factors: KORA F4 study. Cardiovasc Diabetol 2017;16:109
Carstensen-Kirberg M, Kannenberg JM, Huth C, Meisinger C, Koenig W, Heier M, Peters A, Rathmann W, Roden M, Herder C, Thorand B
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”Serum levels of Sfrp5 are associated with a favourable cardiometabolic risk profile: Results from the KORA F4 study” 77. Jahrestagung der American Diabetes Association (ADA), San Diego, CA (USA); 09.–13. Juni 2017
Carstensen-Kirberg M, Kannenberg JM, Huth C, Meisinger C, Koenig W, Peters A, Rathmann W, Roden M, Herder C, Thorand B
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“Antagonistic functions of WNT5A and SFRP5 in hepatic glucose metabolism and inflammation” 54. Jahrestagung der European Association for the Study of Diabetes (EASD), Berlin, 01.-05. Oktober 2018
Carstensen-Kirberg M, Niersmann C, Röhrig K, Roden M, Herder C
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“The Molecular role of WNT5A and its antagonist SFRP5 in gluconeogenesis and inflammation in human hepatocytes” 78. Jahrestagung der American Diabetes Association (ADA), Orlando, FL (USA), 22.–26. Juni 2018
Carstensen-Kirberg M, Niersmann C, Röhrig K, Roden M, Herder C
